TY - JOUR
T1 - Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies
AU - Fernbach, Sonja
AU - Mair, Nina K
AU - Abela, Irene A
AU - Groen, Kevin
AU - Kuratli, Roger
AU - Lork, Marie
AU - Thorball, Christian W
AU - Bernasconi, Enos
AU - Filippidis, Paraskevas
AU - Leuzinger, Karoline
AU - Notter, Julia
AU - Rauch, Andri
AU - Hirsch, Hans H
AU - Huber, Michael
AU - Günthard, Huldrych F
AU - Fellay, Jacques
AU - Kouyos, Roger D
AU - Hale, Benjamin G
AU - Swiss HIV Cohort Study
N1 - © 2024 Fernbach et al.
PY - 2024/9/2
Y1 - 2024/9/2
N2 - Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.
AB - Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.
KW - Humans
KW - Autoantibodies/immunology
KW - Interferon Type I/immunology
KW - Middle Aged
KW - Male
KW - Female
KW - COVID-19/immunology
KW - Antibodies, Neutralizing/immunology
KW - Adult
KW - Aged
KW - SARS-CoV-2/immunology
KW - HIV Infections/immunology
KW - Interferon-alpha/immunology
KW - Retrospective Studies
U2 - 10.1084/jem.20240365
DO - 10.1084/jem.20240365
M3 - Journal article
C2 - 39017930
SN - 0022-1007
VL - 221
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 9
M1 - e20240365
ER -